HRP20021000A2 - PYRROLO[2,3-d]PYRIMIDINE COMPOUNDS AS IMMUNOSUPPRESSIVE AGENTS - Google Patents

Description

Background of the invention

This invention relates to pyrrolo[2,3-d]pyrimidine compounds that are inhibitors of protein kinases, such as the enzyme Janus kinase 3 (hereinafter referred to as JAK3), and these compounds as such can be used for therapeutic purposes as immunosuppressive agents during organ transplantation, xenogeneic transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications resulting from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease , leukemia and other indications in which immunosuppression would be desirable.

This invention also relates to the method of using such compounds in the treatment of the above-mentioned indications in mammals, especially humans, as well as to suitable pharmaceutical preparations thereof.

JAK3 is a member of the Janus protein kinase family. Although other members of this family are expressed by almost all tissues, JAK3 expression is restricted to hematopoietic cells only. This is consistent with its essential role in signaling through receptors for IL-2, IL-4, IL-7, IL-9 and IL-15 through non-covalent associations of JAK3 with the gamma chain shared by these multi-chain receptors. For the XSCID patient population, strongly reduced JAK3 protein levels or genetic defects of the common gamma chain have been observed, indicating that immunosuppression should result from blocking signaling through the JAK3 pathway. Animal studies have shown that JAK3 not only plays a critical role in the maturation of B and T lymphocytes, but also that JAK3 is constitutively required to maintain T cell functions. Modulation of immune activity via this novel mechanism may prove useful in the treatment of disorders of T cell proliferation, such as graft rejection and autoimmune diseases.

The essence of invention

The invention relates to a compound of the formula

[image]

or a pharmaceutically acceptable salt thereof; where

R1 is a group of the formula

[image]

where y is 0, 1 or 2;

R4 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C2-C6)alkenyl, (C2-C6)alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with deuterium , hydroxy, amino, trifluoromethyl, (C1-C4)alkoxy, (C1-C6)acyloxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, cyano, nitro, (C2-C6)alkenyl, ( C2-C6)alkynyl or (C1-C6)acylamino; or R 4 is (C 3 -C 10 )cycloalkyl, wherein the cycloalkyl group is optionally substituted with deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 6 )acyloxy, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkylamino, ((C 1 -C6)alkyl)2amino, cyano, cyano(C1-C6)alkyl, trifluoromethyl(C1-C6)alkyl, nitro, nitro(C1-C6)alkyl or (C1-C6)acylamino;

R 5 is (C 2 -C 9 )heterocycloalkyl, wherein the heterocycloalkyl groups must be substituted with one to five groups consisting of carboxy, cyano, amino, deuterium, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo, ( C1-C6)acyl, (C1-C6)alkylamino, amio(C1-C6)alkyl, (C1-C6)alkoxy-CO-NH, (C1-C6)alkylamino-CO-, (C2-C6)alkenyl, ( C2-C6)alkynyl, (C1-C6)alkylamino, amino(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)acyloxy(C1 -C6)alkyl, nitro, cyano(C1-C6)alkyl, halo(C1-C6)alkyl, nitro(C1-C6)alkyl, trifluoromethyl, trifluoromethyl(C1-C6)alkyl, (C1-C6)acylamino, (C1 -C6)acylamino(C1-C6)alkyl, (C1-C6) alkoxy(C1-C6)acylamino, amino(C1-C6)acyl, amino(C1-C6)acyl(C1-C6)alkyl, (C1-C6 )alkylamino(C1-C6)acyl, ((C1-C6)alkyl)2amino(C1-C6)acyl, R15R16N-CO-O-, R15R16N-CO-(C1-C6)alkyl, (C1-C6)alkyl- S(O)m, R15R16NS(O)m, R15R16NS(O)m(C1-C6)alkyl, R15S(O)mR16N, R15S(O)mR16N(C1-C6)alkyl, where m is 0, 1 or 2 , and R 15 and R 16 are each independently selected from hydrogen or (C 1 -C 6 )alkyl; and formula group

[image]

where a is 0, 1, 2, 3 or 4;

b, c, e, f and g are each independently 0 or 1;

d is 0, 1, 2, or 3;

X is S(O)n, where n is 0, 1 or 2; oxygen, carbonyl or -C(=N-cyano)-;

Y is S(O)n, where n is 0, 1 or 2; or carbonyl; and

Z is carbonyl, C(O)O-, C(O)NR-, where R is hydrogen or (C1-C6)alkyl; or Z is S(O)n, where n is 0, 1 or 2;

R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of hydrogen or (C 1 -C 6 )alkyl optionally substituted with deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 6 )acyloxy, (C 1 -C 6 ) acylamino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, cyano, cyano(C1-C6)alkyl, trifluoromethyl(C1-C6)alkyl, nitro, nitro(C1-C6)alkyl or (C1- C6)acylamino;

R12 is (C6-C10)aryl, (C2-C9)heteroaryl, (C3-C10)cycloalkyl or (C2-C9)heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are optionally substituted with one to four groups forming hydrogen, deuterium, amino, halo, oxo, hydroxy, nitro, carboxy, (C2-C6)alkenyl, (C2-C6)alkynyl, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkosky, (C3 -C10)Cycloalkyl, (C1-C6)alkyl-CO-NH-, (C1-C6)Alkoxy-CO-NH-, (C1-C6)Alkyl-CO-NH-(C1-C6)Alkyl, (C1- C6)Alkoxy-CO-NH-(C1-C6)Alkyl, (C1-C6)Alkoxy-CO-NH-(C1-C6)Alkoxy, Carboxy, Carboxy(C1-C6)Alkyl, Carboxy(C1-C6)Alkoxy , Benzyloxycarbonyl(C1-C6)Alkoxy, (C1-C6)Alkoxycarbonyl(C1-C6)Alkoxy, (C6-C10)Aryl, Amino, Amino(C1-C6)Alkyl, (C1-C6)Alkoxycarbonylamino, (C6-C10 )aryl(C1-C6)Alkoxycarbonylamino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkyl)2amino(C1 -C6)alkyl, Hydroxy, (C1-C6)Alkoxy, Carboxy, Carboxy(C1-C6)Alkyl, (C1-C6)Alkoxycarbonyl, (C1-C6)Alkoxycarbonyl(C1-C6) Alkyl, (C1-C6)Alkoxy-CO-NH-, (C1-C6)Alkyl-CO-NH-, Cyano, (C5-C9)Heterocycloalkyl, Amino-CO-NH-, (C1-C6)Alkylamino-CO -NH-, ((C1-C6)alkyl)2amino-CO-NH-, (C6-C10)arylamino-CO-NH-, (C5-C9)heteroarylamino-CO-NH-, (C1-C6)alkylamino- CO-NH-(C1-C6)alkyl, ((C1-C6)alkyl)2amino-CO-NH-(C1-C6)alkyl, (C6-C10)arylamino-CO-NH-(C1-C6)alkyl, (C5-C9)Heteroarylamino-CO-NH-(C1-C6)Alkyl, (C1-C6)Alkylcyano, (C1-C6)Alkylcarboxy(C1-C6)Alkoxy, (C1-C6)Alkylcarboxy, Sulfonylamino, Aminosulfonyl, Sulfonylamino (C1-C6)alkyl, sulfonylaminocarboxy(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C6-C10)arylsulfonyl, ( C6-C10)arylsulfonylamino, (C6-C10)arylsulfonylamino(C1-C6)alkyl, (C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C3-C10)cycloalkyl, (C3-C10 )cycloalkoxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C6-C10)arylamino, (C1-C6)alkylthio, (C6-C10)arylthio, (C1-C6)alkylsulfinyl, (C6 -C10)arylsulfinyl, (C1-C6)alkylsulfonyl, (C6-C10)arylsulf onyl, (C1-C6)acyl, (C1-C6)alkoxy-CO-NH-, (C1-C6)alkylamino-CO-, (C5-C9)heteroaryl, (C2-C9)heterocycloalkyl or (C6-C10) aryl, wherein the heteroaryl, heterocycloalkyl and aryl groups optionally substituted at R12 may be further substituted with one to three groups comprising halo, (C1-C6)alkyl, (C1-C6)alkyl-CO-NH-, (C1 -C6)Alkoxy-CO-NH-, (C1-C6)Alkyl-CO-NH-(C1-C6)Alkyl, (C1-C6)Alkoxy-CO-NH-(C1-C6)Alkyl, (C1-C6 )Alkoxy-CO-NH-(C1-C6)Alkoxy, Carboxy, Carboxy(C1-C6)Alkyl, Carboxy(C1-C6)Alkoxy, Benzyloxycarbonyl(C1-C6)Alkoxy, (C1-C6)Alkoxycarbonyl(C1-C6 )Alkoxy, (C6-C10)Aryl, Amino, Amino(C1-C6)Alkyl, (C1-C6)Alkoxycarbonylamino, (C6-C10)Aryl(C1-C6)Alkoxycarbonylamino, (C1-C6)Alkylamino, ((C1 -C6)alkyl)2amino, (C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkyl)2amino(C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, carboxy, carboxy(C1 -C6)alkyl, (C1-C6)Alkoxycarbonyl, (C1-C6)Alkoxycarbonyl(C1-C6)Alkyl, (C1-C6)Alkoxy-CO-NH-, (C1-C6)Alkyl-CO-NH-, cyano , (C5-C9)heterocycloalkyl, amino-CO-N H-, (C1-C6)alkylamino-CO-NH-, ((C1-C6)alkyl)2amino-CO-NH-, (C6-C10)arylamino-CO-NH-, (C5-C9)heteroarylamino-CO -NH-, (C1-C6)alkylamino-CO-NH-(C1-C6)alkyl, ((C1-C6)alkyl)2amino-CO-NH-(C1-C6)alkyl, (C6-C10)arylamino- CO-NH-(C1-C6)alkyl, (C5-C9)heteroarylamino-CO-NH-(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino( C1-C6)alkyl, (C6-C10)arylsulfonyl, (C6-C10)arylsulfonylamino, (C6-C10)arylsulfonylamino(C1-C6)alkyl, (C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6 )alkyl, (C5-C9)heteroaryl and (C2-C9)heterocycloalkyl;

R2 and R3 are each independently selected from the group consisting of hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, (C2-C6)alkenyl, (C2-C6)alkynyl, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)Alkoxy, (C3-C10)cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl groups are optionally substituted with one to three groups selected from halo, hydroxy, carboxy, amino(C1-C6)alkylthio, (C1-C6 )alkylamino, ((C1-C6)alkyl)2amino, (C5-C9)heteroaryl, (C2-C9)heterocycloalkyl, (C3-C9)cycloalkyl or (C6-C10)aryl; or R 2 and R 3 are each independently (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkoxy, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl)2amino, (C 6 -C 10 )arylamino, (C 1 -C 6 ) alkylthio, (C6-C10)arylthio, (C1-C6)alkylsulfinyl, (C6-C10)arylsulfinyl, (C1-C6)alkylsulfonyl, (C6-C10)arylsulfonyl, (C1-C6)acyl, (C1-C6)alkoxy -CO-NH-, (C1-C6)alkylamino-CO-, (C5-C9)heteroaryl, (C2-C9)heterocycloalkyl or (C6-C10)aryl, wherein the heteroaryl, heterocycloalkyl and aryl groups are optionally substituted with one up to three of halo, (C1-C6)alkyl, (C1-C6)alkyl-CO-NH-, (C1-C6)alkoxy-CO-NH-, (C1-C6)alkyl-CO-NH-(C1- C6)alkyl, (C1-C6)Alkoxy-CO-NH-(C1-C6)Alkyl, (C1-C6)Alkoxy-CO-NH-(C1-C6)Alkoxy, Carboxy, Carboxy(C1-C6)Alkyl, Carboxy(C1-C6)Alkoxy, Benzyloxycarbonyl(C1-C6)Alkoxy, (C1-C6)Alkoxycarbonyl(C1-C6)Alkoxy, (C6-C10)Aryl, Amino, Amino(C1-C6)Alkyl, (C1-C6 )Alkoxycarbonylamino, (C6-C10)aryl(C1-C6)Alkoxycarbonylamino, (C1-C6)Alkylamino, ((C1-C6)Alkyl)2amino, (C1-C6)Alkylamino(C1-C6)Alkyl, ((C1- C6)alkyl)2amino(C1-C6)alkyl, hydroxy, ( C1-C6)Alkoxy, Carboxy, Carboxy(C1-C6)Alkyl, (C1-C6)Alkoxycarbonyl, (C1-C6)Alkoxycarbonyl(C1-C6)Alkyl, (C1-C6)Alkoxy-CO-NH-, (C1 -C6)alkyl-CO-NH-, cyano, (C5-C9)heterocycloalkyl, amino-CO-NH-, (C1-C6)alkylamino-CO-NH-, ((C1-C6)alkyl)2amino-CO- NH-, (C6-C10)arylamino-CO-NH-, (C5-C9)heteroarylamino-CO-NH-, (C1-C6)alkylamino-CO-NH-(C1-C6)alkyl, ((C1-C6 )alkyl)2amino-CO-NH-(C1-C6)alkyl, (C6-C10)arylamino-CO-NH-(C1-C6)alkyl, (C5-C9)heteroarylamino-CO-NH-(C1-C6) alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C6-C10)arylsulfonyl, (C6-C10)arylsulfonylamino, (C6-C10)arylsulfonylamino( C1-C6)alkyl, (C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C5-C9)heteroaryl or (C2-C9)heterocycloalkyl;

with the proviso that R 5 must be substituted with a group of formula II.

This invention also relates to pharmaceutically acceptable acid addition salts of compounds of formula I. The acids used to prepare pharmaceutically acceptable acid addition salts of the aforementioned basic compounds of this invention are those which form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e. 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)].

The invention also relates to basic addition salts of formula I. Chemical bases that can be used as reagents for preparing pharmaceutically acceptable basic salts of those compounds of formula I which are acidic in nature are those which form non-toxic basic salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations as alkali metal cations (eg, potassium and sodium) and alkaline earth metal cations (eg, calcium and magnesium), ammonium salts, or amine addition salts which are water-soluble ones such as N-methylglucamine-(meglumine), and lower alkanolammonium salts and other basic salts or pharmaceutically acceptable organic amines.

The term "Oxone®" is the name of the monopersulfate compound used in this invention, of the formula 2KHSO5 • KHSO4 • K2SO4, sold by Aldrich Chemical Company, P.O. Box 2060, Milwaukee, WI 53201, USA.

The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched residues or combinations thereof.

The term "Alkoxy" as used herein includes O-alkyl groups, where "alkyl" is as defined above.

The term "halo" as used herein, unless otherwise indicated, includes fluorine, chlorine, bromine or iodine.

The compounds of this invention may contain double bonds. When such linkages are present, the compounds of this invention come in both cis and trans configurations, and as mixtures thereof.

Unless otherwise indicated, the alkyl and alkenyl groups mentioned herein, as well as the alkyl residues and other groups mentioned herein (e.g. alkoxy), may be unbranched or branched, and may also be cyclic (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl), or may be unbranched or branched and may contain cyclic residues. Unless otherwise indicated, halogen includes fluorine, chlorine, bromine and iodine.

(C2-C9)heterocycloalkyl as used herein refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3 -thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl . rings connected through carbon atoms or sp3 hybridized nitrogen as heteroatoms.

(C2-C9)heteroaryl as used herein refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl , 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1 ,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyridinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, tianaphtenyl, isothianaphtenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl, etc. It will be clear to one of skill in the art that said (C2-C9)heteroalkyl rings are linked via a carbon atom or sp3 hybridized nitrogen as a heteroatom.

(C6-C10)aryl as used herein refers to phenyl or naphthyl.

The compounds of formula (I) can be administered in a pharmaceutically acceptable form either alone, or in combination with one or more additional agents that modulate the mammalian immune system or with anti-inflammatory agents. These agents may include, but are not limited to, cyclosporine A (eg, Sandimmune® or Neoral®), rapamycin, FK-506 (Tacrolimus), leflunomide, deoxyspergvaline, mycophenolate (eg, Cellcept®), azathioprine (eg, Imuran®), daclizumab (eg, Zenapax®), OKT3 (eg, Orthoclone®), AtGam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (eg, prednisolone or dexamethasone). These agents may be administered as part of the same or different dosage forms, using the same or different ways of administration, and according to the same or different schedules of administration, in accordance with standard pharmaceutical practice.

The compounds of this invention include all conformational isomers (eg, cis and trans isomers). The compounds of this invention have asymmetric centers, and thus exist in different enantiomeric and diastereomeric forms. The invention relates to the use of all optical isomers and stereoisomers of the compounds of this invention and their mixtures, and to all pharmaceutical preparations and treatment methods in which they can be used or which can contain them. Accordingly, the invention includes both E and Z configurations. Compounds of formula I can also exist as tautomers. This invention relates to the use of all such tautomers and their mixtures.

The present invention also includes pharmaceutical compositions containing prodrugs of the compounds of formula I. The present invention also includes methods of treating or preventing disorders that can be treated or prevented by inhibition of protein kinases, such as the enzyme Janus kinase 3, which include the administration of prodrugs of the compounds of formula I. Compounds formulas I having free amino, amido, hydroxy or carboxyl groups can be converted into prodrugs. Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues that are covalently linked via peptide bonds, are attached to free amino, hydroxy, or carboxyl groups of compounds of formula I. Amino acid residues comprise 20 naturally occurring amino acids, usually designated by three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norveline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds in which carbonates, carbamates, amides and alkyl esters are covalently bound to the above-mentioned substituents of formula I via the carbonyl in the carbon side chain of the prodrug.

Preferred compounds of formula I include those wherein R 5 is (C 2 -C 9 )heterocycloalkyl optionally substituted with one to three groups selected from deuterium, hydroxy, (C 1 -C 6 )alkyl, halo, (C 1 -C 6 )alkoxy and groups of formula II.

Other preferred compounds of formula I include those wherein a is 0; b is 1; X is carbonyl; c is 0; d is 0; e is 0; f is 0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; b is 1; X is carbonyl; c is 0; d is 1; e is 0; f is 0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; b is 1; X is carbonyl; c is 1; d is 0; e is 0; f is 0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; b is 1; X is -C(=N=cyano)-; c is 1; d is 0; e is 0; f is 0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; b is 0; c is 0; d is 0; e is 0; f is 0; g is 1; and Z is -C(O)-O-.

Other preferred compounds of formula I include those wherein a is 0; b is 1; X is S(O)n; n is 2; c is 0; d is 0; e is 0; f is 0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; b is 1; X is S(O)n; n is 2; c is 0; d is 2; e is 0; f is 1; g is 1; and Z is carbonyl.

Other preferred compounds of formula I include those wherein a is 0; b is 1; X is S(O)n; n is 2; c is 0; d is 2; e is 0; f is 1; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; b is 1; X is carbonyl; c is 1; d is 0; e is 1; Y is S(O)n; n is 2; f is 0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; b is 1; X is S(O)n; n is 2; c is 1; d is 0; e is 0; f is 0; and g is 0.

Other preferred compounds of formula I include those wherein a is 1; b is 1; X is carbonyl; c is 1; d is 0; e is 0; f is 0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; b is 1; X is S(O)n; c is 0; d is 1; e is 1; Y is S(O)n; n is 2; f is 0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; b is 1; X is S(O)n; c is 0; d is 1; e is 1; Y is S(O)n; n is 2; f is 1; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; b is 1; X is oxygen; c is 0; d is 1; e is 1; Y is S(O)n; n is 2; f is 1; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; b is 1; X is oxygen; c is 0; d is 1; e is 1; Y is S(O)n; n is 2; f is 0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; b is 1; X is carbonyl; c is 1; d is 1; e is 1; Y is S(O)n; f is 0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; b is 1; X is carbonyl; c is 1; d is 1; e is 1; Y is S(O)n; n is 2; f is 1; and g is 0.

Other preferred compounds of formula I include those wherein R 12 is (C 6 -C 10 )aryl or (C 2 -C 9 )heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with one to four groups consisting of hydrogen, halo, hydroxy, carboxy, trifluoromethyl , (C1-C6)alkyl, (C1-C6)Alkoxy, (C1-C6)alkyl-CO-NH-, amino, amino(C1-C6)alkyl, (C1-C6)alkylamino, ((C1-C6) alkyl)2amino, cyano, amino-CO-NH-, (C1-C6)alkylamino-CO-NH-, ((C1-C6)alkyl)2-CO-NH-, (C5-C9)heteroarylamino-CO-NH -, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylsulfonylamino, (C 6 -C 10 )arylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino and (C 1 -C 6 )alkoxy-CO-NH-.

Specifically preferred compounds of formula I include those wherein said compound is selected from the group consisting of:

4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-ylmethyl}-benzenesulfonamide;

4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-sulfamoyl-phenyl)-amide;

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-nitro-phenyl)-amide;

1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-tetrazol-1-yl-ethanone;

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-methylsulfamoyl-phenyl)-amide;

(3-hydroxy-pyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- methanone;

[2-({4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-carbonyl}-amino)-thiazol-4-yl ]-acetic acid;

Methyl-(4-methyl-5'-nitro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3-yl)-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-amine;

5-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-oxo-ethyl)- thiazolidine-2,4-dione;

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-thiazolidin-3-yl-methanone;

Methyl-[4-methyl-1-(5-nitro-thiazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;

Ethyl ester [2-({4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-amino)-thiazole-4 -yl]-acetic acid;

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-methanesulfonyl-phenyl)-amide;

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid thiazol-2-ylamide;

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-cyano-phenyl)-amide;

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-pyrrolidin-1-yl-methanone;

(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-sulfonyl}-ethyl)-amide furan-2-carboxylic acids;

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl} (tetrahydro-furan-3-yl)-methanone;

4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid isoxazol-3-ylamide;

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (6-cyano-pyridin-3-yl)amide;

4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl- 5'-carbonitrile;

(4-methyl-thiazol-2-yl)-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic group;

2-cyclopropyl-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone;

Cyclopentyl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone;

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (3-methyl-isoxazol-4-yl)-amide;

[4-({4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-amino)-phenyl]-acetic acid ;

[1-(5-amino-thiazol-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (3-methyl-isothiazol-5-yl)-amide;

3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-cyclopentanone;

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid benzyl-methyl-amide; and

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid dimethylamide;

This invention also relates to a pharmaceutical composition for (a) treating or preventing disorders or conditions selected from organ transplant rejection, xenograft rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications resulting from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune disorders, or (b) inhibition of protein kinases or Janus kinase 3 (JAK3), in mammals, including humans, which the preparation contains an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, which is effective in such disorders or conditions, and a pharmaceutically acceptable carrier.

This invention also relates to a method of inhibiting protein tyrosine kinase or Janus kinase 3 (JAK3) in a mammal, including a human, which method consists in applying to said mammal an effective amount of the compound of formula I or its pharmaceutically acceptable salt.

This invention also relates to a method of treating or preventing disorders or conditions selected from organ transplant rejection, xenogeneic transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications resulting from diabetes, cancer, asthma, atopic dermatitis, autoimmune disorders of the thyroid, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune disorders, in mammals, including humans, which procedure consists in applying to said mammal an amount of the compound of formula I or its pharmaceutically acceptable salt, which is effective in the treatment such conditions.

Detailed description of the invention

The following reaction schemes illustrate the preparation of the compounds of this invention. R2, R3, R4 and R5 in the reaction schemes and in the following discussion, unless otherwise indicated, are defined as in the previous text.

The procedure for obtaining A

[image]

The procedure for obtaining B

[image]

The procedure for obtaining C

[image]

Scheme 1

[image]

Scheme 2

[image]

Scheme 3

[image]

In reaction 1 of Method A, the 4-chloropyrrolo[2,3-d]pyrimidine compound of formula XXI, where R is hydrogen or a protecting group such as benzenesulfonyl or benzyl, is converted to 4-chloro-5-halopyrrolo[2,3 -d]pyrimidine compound of formula XX, where Y is chlorine, bromine or iodine, by reaction of compound XXI with N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide. The reaction mixture is heated at reflux, in chloroform, for a period of time from about 1 hour to about 3 hours, preferably about 1 hour. Alternatively, in reaction 1 of Process A, 4-chloropyrrolo[2,3-d]pyrimidine of formula XXI, where R is hydrogen, is converted to the corresponding 4-chloro-5-nitropyrrolo[2,3-d]pyrimidine of formula XX, where Y is nitro, by reacting compound XXI with nitric acid in sulfuric acid at a temperature of about -10°C to about 10°C, preferably about 0°C, for a time period of about 5 minutes to about 15 minutes, preferably about 10 minutes. A compound of formula XXI, where Y is nitro, is converted into the corresponding 4-chloro-5-aminopyrrolo[2,3-d]pyrimidine of formula XX, where Y is amino, by reacting compound XXI under various conditions well known to those skilled in the art. such as hydrogenolysis with palladium or stannous chloride and hydrochloric acid.

In reaction 2 of Method A, the 4-chloro-5-halopyrrolo[2,3-d]pyrimidine compound of formula XX, where R is hydrogen, is converted into the corresponding compound of formula XIX, where R 2 is (C 1 -C 6 )alkyl or benzyl , by treating compound XX with N-butyllithium, at a temperature of about -78 °C, and reacting the dianionic intermediate thus obtained with an alkyl halide or benzyl halide at a temperature of about -78 °C to room temperature, preferably at room temperature. Alternatively, the dianion thus obtained reacts with molecular oxygen to form the corresponding 4-chloro-5-hydroxypyrrolo[2,3-d]pyrimidine compound of formula XIX, wherein R 2 is hydroxy. A compound of formula XX, where Y is bromine or iodine and R is benzenesulfonate, is converted into a compound of formula XIX, where R2 is (C6-C12)aryl or vinyl, by treating compound XX with N-butyllithium at a temperature of about -78 °C , followed by the addition of zinc chloride, at a temperature of about -78 °C. The corresponding organozinc intermediate thus obtained is then reacted with aryl iodide or vinyl iodide in the presence of a catalytic amount of palladium. The reaction mixture is stirred at a temperature of about 50°C to about 80°C, preferably about 70°C, for a time period of about 1 hour to 3 hours, preferably about 1 hour.

In reaction 3 of Process A, the compound of formula XIX is converted into the corresponding compound of formula XVI by treating compound XIX with N-butyllithium, lithium diisopropylamine or sodium hydride, at a temperature of about -78 °C, in the presence of a polar aprotic solvent, as which is tetrahydrofuran. The anionic intermediate thus obtained is further reacted with (a) alkyl halide or benzyl halide, at a temperature of about -78 °C to room temperature, preferably -78 °C, in the case where R 3 is alkyl or benzyl; (b) with an aldehyde or a ketone, at a temperature of about -78 °C to room temperature, preferably -78 °C, in the case where R 3 is alkoxy; and (c) with zinc chloride, at a temperature of about -78 °C to room temperature, preferably -78 °C, and the corresponding organozinc intermediate thus obtained is then reacted with aryl iodide or vinyl iodide in the presence of a catalytic amount palladium. The resulting reaction mixture is stirred at a temperature of about 50 °C to about 80 °C, preferably about 70 °C, for a time period of about 1 hour to 3 hours, preferably about 1 hour. Alternatively, the anion thus obtained reacts with molecular oxygen to form the corresponding 4-chloro-6-hydroxypyrrolo[2,3-d]pyrimidine compound of formula XVI, wherein R 3 is hydroxy.

In reaction 1 of Preparation B, the 4-chloropyrrolo[2,3-d]pyrimidine compound of formula XXI is converted into the corresponding compound of formula XXII, according to a procedure analogous to that described above in reaction 3 of Preparation A.

In reaction 2 of Preparation Process B, the compound of formula XXII is converted into the corresponding compound of formula XVI, according to procedures analogous to those described above in reactions 1 and 2 of Preparation Process A.

In reaction 1 of Process C, the 4-methylpyridine compound of formula XXXI is converted to the corresponding compound of formula XXX by first alkylating compound XXXI with benzyl chloride in the presence of a polar aprotic solvent, such as acetone. The reaction mixture is stirred at a temperature of about 40°C to about 80°C for a time period of about 4 hours to about 24 hours. The pyridinium intermediate thus obtained is then reduced using a reducing agent such as sodium boron hydride in the presence of a polar protic solvent such as methanol, ethanol, water and mixtures thereof. The reaction is stirred at a temperature of from about 0 °C to about room temperature, for a period of time from about 18 hours to 24 hours.

In reaction 2 of Process C, a compound of formula XXX is converted to the corresponding compound of formula XXIX by treating compound XXX with boron trifluoride etherate in the presence of a reducing agent and a protic solvent, such as tetrahydrofuran. The reaction mixture is stirred at a temperature of from about 0°C to room temperature for a period of time from about 1 hour to about 3 hours. The resulting intermediate complex is then alkalized using an aqueous solution of sodium hydroxide, after which it is treated with an oxidant such as hydrogen peroxide or Oxone®, at a temperature from about 0 °C to room temperature, for a period of time from about 12 hours to about 24 hours.

In reaction 3 of Process C, the compound of formula XXIX is treated with an oxidant, such as chromium oxide or dimethyl sulfoxide, oxalyl chloride, or SO 3 -pyridine complex, for a time period of about 1 hour to 3 hours, at room temperature. The intermediate ketone thus obtained is then treated with an amine (R 4 -NH 2 ) in the presence of an acid, such as acetic acid, at room temperature, for a time period of about 2 to about 24 hours, in an organic solvent such as methanol, ethanol, or tetrahydrofuran. . The corresponding imine intermediate thus obtained is then treated with a reducing agent, such as sodium boron hydride or sodium cyanoborohydride or sodium triacetoxyborohydride, at room temperature for a time period of about 2 hours to about 24 hours.

In reaction 1 of Scheme 1, the 4-chloropyrrolo[2,3-d]pyrimidine compound of formula XVII is converted into the corresponding compound of formula XVI, where R is benzenesulfonyl or benzyl, by treating compound XVII with benzenesulfonyl chloride, benzyl chloride or benzyl bromide , in the presence of a base such as sodium hydride or potassium carbonate, and in the presence of a polar aprotic solvent such as dimethylformamide or tetrahydrofuran. The reaction mixture is stirred at a temperature of about 0 °C to about 70 °C, preferably about 30 °C, for a time period of about 1 hour to about 3 hours, preferably about 2 hours.

In reaction 2 of Scheme 1, the 4-chloropyrrolo[2,3-d]pyrimidine compound of formula XVI is converted into the corresponding 4-aminopyrrolo[2,3-d]pyrimidine compound of formula XV, by condensation of compound XVI with the amine of formula NHR4R5. The reaction is carried out in an alcoholic solvent such as tert-butanol, methanol or ethanol, or another high-boiling organic solvent such as dimethylformamide, triethylamine, 1,4-dioxane or 1,2-dichloroethane, at a temperature of about 60 °C up to about 120 °C, preferably about 80 °C. Typical reaction times are about 2 hours to about 48 hours, preferably about 16 hours. When R 5 is a nitrogen-containing heterocycloalkyl group, each nitrogen must be protected by a protecting group, such as benzyl. Removal of the R5 protecting group is performed under conditions appropriate to the particular protecting group used and which will not affect the R protecting group on the pyrrolo[2,3-d]pyrimidine ring. Removal of the R5 protecting group when it is benzyl is carried out in an alcoholic solvent such as ethanol, in the presence of hydrogen, and a catalyst such as palladium hydroxide on carbon. The nitrogen-containing R5 heterocyclic group thus formed can further react with a large number of different electrophiles of formula II. To form urea, electrophiles of formula II such as isocyanates, carbamates and carbamoyl chlorides are reacted with the R5 nitrogen of a heteroalkyl group in a solvent such as acetonitrile or dimethylformamide, in the presence of a base such as sodium carbonate or potassium carbonate, at a temperature of about 20 °C to about 100 °C, over a time period of about 24 hours to about 72 hours. To form amides and sulfonamides, electrophiles of formula II such as acyl chlorides and sulfonyl chlorides are reacted with the R5 nitrogen of a heteroalkyl group in a solvent such as methylene chloride, in the presence of a base such as pyridine, at room temperature for a time period of about 12 hours to about 24 hours. Amide formation can also be performed by reacting a carboxylic acid with a heteroalkyl group in the presence of a carbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, in a solvent such as methylene chloride at ambient temperature for 12-24 hours. To form alkyl, electrophiles of formula II such as �,�-unsaturated amides, acids, nitriles, esters and �-halo amides are reacted with the R5 nitrogen of a heteroalkyl group, in a solvent such as methanol at room temperature, for a time period of approx. 12 o'clock until about 6 p.m. Alkyl formation can also be performed by reacting an aldehyde with a heteroalkyl group, in the presence of a reducing agent such as sodium cyanoborohydride, in a solvent such as methanol at ambient temperature, for a time period of about 12 hours to about 18 hours.

In reaction 3 of Scheme 1, deprotection of a compound of formula XV where R is benzenesulfonyl to give the corresponding compound of formula I is performed by treating compound XV with an alkaline base, such as sodium hydroxide or potassium hydroxide, in an alcoholic solvent such as methanol or ethanol, or in mixed solvents such as alcohol/tetrahydrofuran or alcohol/water. The reaction is carried out at room temperature, during a time period of about 15 minutes to about 1 hour, preferably 30 minutes. Removal of the protecting group from the compound of formula XV, where R is benzyl, is performed by treating compound XV with sodium, in ammonia at a temperature of about -78°C, for a time period of about 15 minutes to about 1 hour.

In reaction 1 of Scheme 2, the 4-chloropyrrolo[2,3-d]pyrimidine compound of formula XX is converted into the corresponding 4-aminopyrrolo[2,3-d]pyrimidine compound of formula XXIV, according to a procedure analogous to that described previously in reaction 2 of Scheme 1 .

In reaction 2 of Scheme 2, the 4-amino-5-halopyrrolo[2,3-d]pyrimidine compound of formula XXIV, where R is benzenesulfonate and Z is bromine or iodo, is converted to the corresponding compound of formula XXIII by reacting compound XXIV with: (a ) with an arylboronic acid, in the case where R 2 is aryl, in an aprotic solvent, such as tetrahydrofuran or dioxane, in the presence of a catalytic amount of palladium(0), at a temperature of about 50 °C to about 100 °C, preferably about 70 °C, during a period of time from about 2 hours to about 48 hours, preferably about 12 hours; (b) alkynes, in the case where R2 is alkynyl, in the presence of a catalytic amount of copper(I)-iodide and palladium(0), and a polar solvent such as dimethylformamide, at room temperature, for a period of time from about 1 hour to about 5 hours, preferably around 3 hours; and (c) alkenes or styrenes, in the case where R 2 is vinyl or styrenyl, in the presence of a catalytic amount of palladium in dimethylformamide, dioxane or tetrahydrofuran, at a temperature of from about 2 hours to about 48 hours, preferably about 48 hours.

In reaction 3 of Scheme 2, the compound of formula XXIII is converted into the corresponding compound of formula XV, according to a procedure analogous to that described above in reaction 3 of Preparation Process A.

In reaction 1 of Scheme 3, the compound of formula XVII is converted into the corresponding compound of formula I, according to a procedure analogous to that previously described in reaction 2 of Scheme 1.

The compounds of this invention which are basic in nature can form a variety of salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for use in animals, in practice it is often desirable to first isolate the compound of this invention from the reaction mixture as a pharmaceutically unacceptable salt, which is then simply converted back to the free base of the compound by treatment with an alkaline reagent, which is finally translated into a pharmaceutically acceptable acid salt. Acid salts of the basic compounds of this invention can be readily prepared by treating the basic compound with substantially the same amount of a selected mineral or organic acid, in an aqueous solvent or in a suitable organic solvent, such as methanol or ethanol. By carefully evaporating the solvent, the desired solid salt is easily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding the appropriate mineral or organic acid to the solution.

The compounds of this invention, which are acidic in nature, are capable of forming basic salts with various pharmacologically acceptable cations. Examples of such salts include alkali and alkaline earth metal salts, especially sodium and potassium salts. All these salts are prepared using conventional techniques. The chemical bases used as reagents for the preparation of the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acid compounds of this invention. Such non-toxic basic salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium, etc. These salts can be readily prepared by treating the appropriate acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, followed by evaporation of the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing solutions of acidic compounds in lower alkanols with an alkoxide of the desired alkali metal, followed by evaporation of the resulting solution to dryness, in the same manner as before. In all cases, it is preferable to use stoichiometric amounts of reagents, in order to ensure the completeness of the reaction and maximize the yield of the desired final product.

The compositions of this invention may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients. Accordingly, the active compounds of the present invention may be formulated for oral, intranasal, parenteral (eg, intravenous, intramuscular, or subcutaneous) or rectal administration, or in a form suitable for administration by inhalation or insufflation. The active compounds of the invention can also be formulated for extended delivery.

Pharmaceutical preparations intended for oral administration may be in the form of, for example, tablets or capsules, which are prepared in a conventional manner with pharmaceutically acceptable excipients such as binders (eg pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (eg lactose, microcrystalline cellulose or calcium phosphate); lubricants (eg magnesium stearate, talc or silicon dioxide); disintegrants (eg potato starch or sodium starch glycolate); or wetting agents (eg, sodium lauryl sulfate). The tablets may be coated using methods well known in the art. Liquid preparations intended for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be dry products which are reconstituted with water or some other suitable vehicle before use. Such liquid preparations may be prepared in a conventional manner with pharmaceutically acceptable additives such as suspending agents (eg sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (eg lecithin or gum arabic); non-aqueous vehicles (eg almond oil, oil esters or ethyl alcohol); and preservatives (eg, methyl or propyl p-hydroxybenzoates or sorbic acid).

Preparations intended for buccal administration may be in the form of tablets or lozenges formulated in a conventional manner.

The active compounds of the invention may be formulated for parenteral administration by injection, including the use of conventional catheterization or infusion techniques. Formulations for injections can be prepared in the form of individual doses, for example in ampoules or multi-dose containers, with the addition of preservatives. Such preparations may be in forms such as suspensions, solutions or emulsions in oily or aqueous carriers, and may also contain formulation agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient can be in the form of a powder that is reconstituted with a suitable carrier before use, eg sterile pyrogen-free water.

The active compounds of the invention may also be formulated into rectal preparations such as suppositories or retention enemas, eg by containing conventional suppository bases such as cocoa butter or other glycerides.

For intranasal or inhalation administration, the active compounds of the invention are conveniently delivered as solutions or suspensions from a patient-squeezed or pumped spray pump container, or by delivery of an aerosol spray from a pressurized container or nebulizer, using a suitable propellant gas, e.g., dichlorodifluoromethane. , trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or any other suitable gas. In the case of pressurized aerosols, the dosage form can be equipped with a valve that will release a metered amount. A pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, of gelatin) for use in an inhaler or insufflator can be formulated to contain a powder mixture of a compound of the invention with a suitable powder carrier, such as lactose or starch.

A suggested dose of the active compounds of the invention for oral, parenteral or buccal administration intended for the treatment of the aforementioned conditions (e.g. rheumatoid arthritis) in an average adult is 0.1 to 1,000 mg of active ingredient per unit dose that can be administered, for example, 1 to 4 times a day.

Aerosol formulations intended for the treatment of the aforementioned conditions (eg, asthma) in the average adult are preferably prepared such that each metered dose or "puff" of the aerosol contains 20 µg to 1,000 µg of a compound of the invention. The total daily aerosol dose will be in the range of 0.1 mg to 1000 mg. The administration can be several times a day, for example, 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses each time.

The compounds of formula (I) are administered in a pharmaceutically acceptable form either alone, or in combination with one or more additional agents that modulate the mammalian immune system, or with anti-inflammatory agents, and these agents may include, but are not limited to, cyclosporine A (eg, Sandimmune ® or Neoral®, rapamycin, FK-506 (Tacrolimus), leflunomide, deoxyspergvaline, mycophenolate (eg Callcept®), azathioprine (eg Imuran®), daclizumab (eg Zenapax®), OKT3 (eg Orthocolone®), AtGam , aspirin, actaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (eg, prednisolone or dexamethasone), and such agents may be administered as part of the same or different dosage forms, using the same or different routes of administration, and according to the same or different administration schedules, in accordance with standard pharmaceutical practice.

FK506 (Tacrolimus) is administered orally in a dose of 0.10-0.15 mg/kg of body weight, every 12 hours, within the first 48 hours postoperatively. The dose is monitored through the level of Tacrolimus in the serum.

Cyclosporine A (Sandimmune oral or intravenous formulation, or Neoral® oral solution or capsules) is given orally at a dose of 5 mg/kg body weight, every 12 hours, within 48 hours postoperatively. The dose is checked by the level of Cyclosporin A in the blood.

Active agents can be formulated for sustained delivery using procedures well known to those skilled in the art. Examples of such formulations can be found in US Patents 3,538,214; 4,060,598; 4,173,626; 3,119,742 and 3,492,397.

The ability of the compounds of formula I or their pharmaceutically acceptable salts to inhibit Janus kinase 3, and therefore to demonstrate their efficacy in the treatment of disorders or conditions characterized by Janus kinase 3, is demonstrated by the following in vitro assays.

Biological analysis

Enzymatic analysis of JAK3 (JH1:GST)

The JAK3 kinase assay uses a protein expressed in baculovirus-infected SF9 cells (a fusion protein of GST and the catalytic domain of human JAK3), which was purified by glutathione-sepaharose affinity chromatography. The substrate for the reaction is poly-glutamic acid-tyrosine (PGT (4:1), Sigma, catalog number P0275). Nunc Maxi Sorp tablets were coated with it at a concentration of 100 µg/ml overnight at 37 °C. The morning after plating, plates were washed three times, and JAK3 was added to wells containing 100 µl of kinase buffer (50 mM HEPES, pH 7.3, 125 mM NaCl, 24 mM MgCl2) + 0.2 µM ATP + 1 mM Na orthovanadate.) The reaction lasted 30 minutes at room temperature, after which the plates were washed three more times. The level of phosphorylated tyrosine in a well was determined by standard ELISA analysis using anti-phosphotyrosine antibody (ICN PY20, catalog number 69-151-1).

IL-2-dependent inhibition of human T-lymphoblast proliferation

This assay measures the inhibitory effect of compounds on IL-2-dependent T-lymphoblast proliferation in vitro. Because signaling by the IL-2 receptor requires JAK3, active cellular inhibitors of JAK-3 should inhibit IL-2-dependent T-lymphoblast proliferation.

The cells for this analysis were isolated from fresh human blood. After separation of mononuclear cells using the Accuspin System-Histopaque-1077 (Sigma, catalog number A7054), primary human T-cells were isolated by negative selection using Lympho-Kwik T (One Lambda, Inc., catalog number LK-50T). T cells were grown to 1-2 × 106/ml in media (RPMI + 10% heat-inactivated fetal calf serum (Hyclone, catalog number A-1111-L) + 1% penicillin/streptomycin (Gibco)), and stimulated at proliferation by adding 10 ug/ml PHA (Murex Diagnosis, catalog number HA 16). After 3 days at 37 °C in 5% CO2, cells were washed three times in media, resuspended to a density of 1-2 × 106 cells/ml in media supplemented with 100 units/ml of human recombinant IL-2 (R&D Systems, catalog number 202-IL). After 1 week, the cells are dependent on IL-2, and can be maintained for up to 3 weeks by feeding them twice a week with the same volumes of media + 100 units/ml IL-2.

To analyze the ability of test compounds to inhibit IL-2-dependent T-cell proliferation, IL-2-dependent cells were washed three times, resuspended in media, and then plated (50,000 cells/well/0.1 ml) in a microtiter plate with 96-well flat bottom (Falcon, catalog number 353075). From a 10 mM stock solution of the test compound in DMSO, serial duplicate solutions of the compound were added in triplicate to the wells starting at 10 µM. After 1 hour, 10 units/ml IL-2 is added to each tested well. The plates were then incubated at 37 °C, 5% CO2 for 72 hours. After that, the plates are labeled with 3H-thymidine (0.5 uCi/well) (NEN, catalog number NET-027A) and incubated for another 18 hours. Plate cultures were then harvested using a 96-well plate harvester, after which the amount of 3H-thymidine incorporated into proliferating cells was determined by counting on a Packard Top Count scintillation counter. The data were analyzed using a graphical display of % inhibition of proliferation as a function of the concentration of the tested compound. The IC50 value (uM) was determined from this graph.

The following examples illustrate the preparation of the compounds of this invention, the invention not being limited to the details given therein. Commercial reagents were used without additional purification. THF refers to tetrahydrofuran. DMF refers to N,N-dimethylformamide. Low Resolution Mass Spectra (LRMS) were recorded either with a Hewlett Packard 5989® using chemical ionization (ammonium), or with a Fisons (or Micro Mass) Atmospheric Pressure Chemical Ionization (APCI) platform using a 50/50 mixture of acetonitrile /water with 0.1% formic acid as an ionizing agent. Room temperature refers to 20-25 °C.

Example 1

Furan-2-yl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone

Method A 1-benzyl-4-methyl-pyridinium chloride

31 ml (0.268 mol) of benzyl chloride is added to a mixed solution of 4-methylpyridine (26 ml/0.268 mol) in 70 ml of acetone. The resulting mixture is stirred at 50 °C for 18 hours. After cooling to room temperature, the reaction was filtered, washed with acetone and dried under reduced pressure to give 38 g of the title compound. The filtrate was concentrated under reduced pressure to give an additional 5.6 grams of the title compound (74% overall yield).

LRMS: 184.

Method B 1-benzyl-4-methyl-1,2,3,6-tetrahydro-pyridine

To a stirred solution of the product from Process A (38 grams/0.171 mole) dissolved in 140 ml of 10:1 ethanol/water at 0°C is added 16 grams (0.427 mole) of sodium boron hydride in portions over 25 minutes. The resulting mixture is stirred for 18 hours at room temperature, after which the reaction is quenched by adding 100 ml of water. The reaction mixture is filtered, the filter cake is washed with water and ethyl acetate, and the filtrates collected together are concentrated under reduced pressure to remove organic substances. The residue was diluted with water (100 ml) and extracted three times with 150 ml of ethyl acetate. The combined ethyl acetate extracts were dried over Na2SO4 and concentrated to dryness in vacuo to give 32 grams (100%) of the title compound as a yellow oil.

LRMS: 188 (M+1).

Method C 1-benzyl-4-methyl-piperidin-3-ol

To a solution of the product from Procedure B (72.45 grams/0.387 mol) dissolved in 240 ml of THF, 21.4 grams of NaBH4 was added and the mixture was cooled to 0 °C. After that, a solution of boron trifluoride ether (109.4 ml dissolved in 200 ml THF) is added dropwise over 1.5 hours. The reaction mixture is then warmed to room temperature and stirred for 2 hours. The reaction was cooled again to 0 °C, after which 29.3 ml of water was added dropwise over 15 minutes, and then 2N sodium hydroxide (97.5 ml) was added dropwise over 20 minutes. The resulting mixture is stirred at 0 °C for 40 minutes, after which it is heated to room temperature. Hydrogen peroxide (30%) (97.5 ml) is added dropwise to the reaction mixture so that the temperature does not exceed 50 °C (approximately 30 minutes). When the addition is complete, the reaction mixture is stirred for 10 minutes and then cooled to 0 °C. Concentrated hydrochloric acid (97.5 ml) was added over 5 minutes, after which the reaction mixture was reduced to one third of its volume in vacuo and the pH was adjusted to 9-10 with 6N sodium hydroxide (aqueous solution). The resulting mixture was extracted three times with ether, and the combined ether layers were dried over MgSO4 and evaporated to dryness in vacuo to give 65.32 grams (79%) of the title compound as a yellow oil.

LRMS: 206.1 (M+1).

Alternative procedure: To a solution of the product from Procedure B (18.7 grams/0.1 mol) in THF (150 ml) is added NaBH4 (6.5 grams/0.170 mol) at room temperature under an atmosphere of N2. The precipitate was cooled to 0 °C, after which BF 3 • OEt 2 (15 mL, 16.8 grams/0.118 mol) in THF (25 mL) was slowly added via addition funnel. The addition must be slow enough to keep the temperature of the reaction mixture below 0 °C. After the addition was complete, the reaction mixture was stirred at 0 °C for 1 hour and then at room temperature for 1.5 hours. The reaction was cooled again to 0 °C, after which water (50 ml) was slowly added to destroy excess boron. The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of Oxone® (110 grams/0.343 mol) in water (500 ml) at 0 °C. The reaction mixture was allowed to warm to room temperature, after which it was stirred overnight. The reaction is quenched by adding solid NaHSO3 until the excess oxidant is destroyed (KI/starch test paper). The pH of the reaction mixture is 1-2. The reaction mixture is then extracted three times with 50 ml of ethyl acetate, and the aqueous layer is brought to pH 12 by the addition of 6N sodium hydroxide, after which it is extracted with ethyl acetate (four times with 100 ml). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give 19.0 grams (92%) of the title compound as an oil.

LRMS: 206.1 (M+1).

Procedure D 1-Benzyl-4-methyl-piperidin-3-ol-toluene-4-sulfonic acid salt

To the mixed solution of the product from Procedure C (65.32 grams/0.318 moles) which was dissolved in 175 ml of acetone and cooled to 0 °C, a solution of paratoluenesulfonic acid monohydrate in 350 ml of acetone (in drops) was added over 2 hours, and the resulting mixture stirred at 0 °C for 1.5 hours. The precipitate is filtered, and the filter cake is washed with 90 ml of diisopropyl ether. The solid product was then dried in vacuo to give 58.55 grams (100%) of the title compound as a white solid.

LRMS: 378.5 (M+1).

Method E 1-benzyl-4-methyl-piperidin-3-one

12.4 grams of SO3-pyridine complex dissolved in 153 ml of dimethylsulfoxide for 40 minutes. The reaction is then stirred for 1.5 hours at room temperature, after which it is quenched by adding 200 ml of saturated NaHCO3 (aqueous solution). The dichloromethane is removed in vacuo and the remaining aqueous residue is extracted four times with diisopropyl ether (150 ml). The combined ether layers were washed four times with water (100 mL), dried over Na 2 SO 4 , and concentrated to dryness in vacuo to give 3.81 grams (72.97 %) of the title compound as a yellow oil.

LRMS: 204 (M+1).

Method F (1-benzyl-4-methyl-piperidin-3-yl)-methyl-amine

2.2 ml of acetic acid is added to a mixed solution of the product from Procedure E (3.81 grams/0.019 moles) and 38 ml of 2.0 M methylamine in THF, and the resulting mixture is stirred at room temperature for 1.5 hours. Sodium triacetoxyborohydride (NaB(OAc)3H) (7.94 grams/0.038 moles) was added as a solid, and the resulting mixture was stirred at room temperature for 18 hours. The reaction is quenched by the addition of 2N hydrochloric acid and the pH is adjusted to 1. The reaction mixture is washed twice with ether, after which the pH of the aqueous layer is adjusted to 12 by the addition of 6N sodium hydroxide (aqueous solution) and extracted three times with dichloromethane. The combined dichloromethane layers were dried over Na 2 SO 4 , filtered and evaporated to dryness in vacuo to give 3.51 grams (87.75 %) of the title compound as a dark yellow oil.

LRMS: 219.1 (M+1).

Method G (1-benzyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

A mixture of 4-chloropyrrolo[2,3-d]pyrimidine (2.4 grams, 15.9 mmol) prepared according to the procedure described by Davoll in "J. Am. Chem. Soc.", 82, 131, (1960) , the product from Procedure F (1.7 grams, 7.95 mmol) and 10 ml of triethylamine was heated in a closed tube at 100 °C for 4 days. After cooling to room temperature and concentration under reduced pressure, the residue was purified by flash chromatography (silica; 3% methanol in dichloromethane) to give 1.0 grams (38%) of the title compound as a colorless oil.

LRMS: 336.1 (M+1).

Method H Methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

To the product from Procedure G (0.7 grams, 2.19 mmol) dissolved in 15 ml of ethanol was added 0.5 grams of 20% palladium hydroxide on carbon (50% water) (Aldrich), and the resulting mixture was shaken ( Parr shaker) under a hydrogen atmosphere (50 psi) at room temperature for 2 days. The reaction mixture was filtered through Celite and concentrated in vacuo to dryness, and the residue was purified by flash chromatography (silica; 5% methanol in dichloromethane) to give 0.48 grams (90%) of the title compound.

LRMS: 246.1 (M+1).

Procedure I [1-(4-Methoxy-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

40 mg (0.163 mmol) of the product from Procedure H and 20 l of 4-methoxy-benzenesulfonyl chloride are added to a mixed solution of 1 ml of pyridine and 9 ml of dichloromethane, and the resulting mixture is stirred at room temperature for 18 hours. The reaction is quenched by adding saturated NaHCO3 (aqueous solution), after which the organic layer is removed, and the aqueous layer is extracted with dichloromethane. The dichloromethane layer is dried over Na2SO4 and concentrated in vacuo. The residue was purified by PTLC (silica; 10:1 dichloromethane/methanol) to give 22 mg (32%) of the title compound as a pale yellow oil. LRMS: 416.5 (M+1).

The title compounds for Examples 2-297 were obtained by a procedure analogous to that described in Example 1.

Example 2

[1-(4-Methoxy-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 416.

Example 3

(1-benzenesulfonyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 386.

Example 4

2-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-sulfonyl}-ethyl)-isoindole-1, 3-dione

LRMS: 483.

Example 5

Cyclohexanecarboxylic acid 2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-amide

LRMS: 463.

Example 6

2-chloro-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-piperidin-1-sulfonyl}-ethyl)-benzamide

LRMS: 492.

Example 7

4-chloro-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)- benzamide

LRMS: 492.

Example 8

(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-sulfonyl}-ethyl)-amide furan-2-carboxylic acid

LRMS: 447.

Example 9

3-methoxy-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)- benzamide

LRMS: 487.

Example 10

(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-amide isoxazole-5-carboxylic acid

LRMS: 448.

Example 11

2,4-difluoro-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl )-benzamide

LRMS: 493.

Example 12

3-chloro-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)- benzamide

LRMS: 492.

Example 13

3-fluoro-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)- benzamide

LRMS: 475.

Example 14

2-fluoro-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)- benzamide

LRMS: 475.

Example 15

4-fluoro-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)- benzamide

LRMS: 475.

Example 16

N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-sulfonyl}-ethyl)-benzamide

LRMS: 457.

Example 17

Cyclopropanecarboxylic acid (2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-amide

LRMS: 421.

Example 18

Cyclopentanecarboxylic acid (2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-amide

LRMS: 449.

Example 19

Cyclopentyl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone

LRMS: 342.

Example 20

(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-sulfonyl}-ethyl)-amide tetrahydro-furan-2 -carboxylic acids

LRMS: 451.

Example 21

(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-sulfonyl}-ethyl)-amide tetrahydro-furan-3 -carboxylic acids

LRMS: 451.

Example 22

{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}(tetrahydro-furan-2-yl)-methanone

LRMS: 344.

Example 23

{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}(tetrahydro-furan-3-yl)-methanone

LRMS: 344.

Example 24

(3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propyl)-amide

LRMS: 427.

Example 25

2-cyclopropyl-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone

LRMS: 328.

Example 26

2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-pyrrolidine-1-carboxylic acid tert-butyl ester

LRMS: 443.

Example 27

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-pyrrolidin-2-yl-methanone

LRMS: 343.

Example 28

1-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-carbonyl}-pyrrolidin-1-yl)- ethanone hydrochloride

LRMS: 385.

Example 29

Furan-3-yl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone

LRMS: 340.

Example 30

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-pyridin-2-yl-methanone

LRMS: 351.

Example 31

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-phenyl-methanone

LRMS: 350.

Example 32

1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-phenyl-ethanone

LRMS: 364.

Example 33

2-cyclopropyl-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone hydrochloride

LRMS: 364.

Example 34

2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-pyrrolidine-1-carboxylic acid tert-butyl ester

LRMS: 443.

Example 35

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid benzylamide

LRMS: 379.

Example 36

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid phenylamide

LRMS: 365.

Example 37

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid tetrahydro-furan-3-yl ester

LRMS: 360.

Example 38

1-(4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-carbonyl}-piperidin-1-yl)- ethanone

LRMS: 399.

Example 39

2-cyclopentyl-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone

LRMS: 356.

Example 40

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid cyclohexamide

LRMS: 371.

Example 41

Azetidin-3-yl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone trifluoroacetate

LRMS: 443.

Example 42

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-pyrrolidin-1-yl-methanone

LRMS: 343.

Example 43

Methyl-phenyl-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid

LRMS: 379.

Example 44

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-morpholin-4-yl-methanone

LRMS: 359.

Example 45

Methyl-(4-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- Amen

LRMS: 323.

Example 46

Methyl-(4-methyl-1-thiazol-2-yl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 329.

Example 47

Pyridin-3-ylamide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid

LRMS: 366.

Example 48

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-fluoro-phenyl)-amide

LRMS: 383.

Example 49

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-nitro-phenyl)-amide

LRMS: 410.

Example 50

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-methoxy-phenyl)-amide

LRMS: 395.

Example 51

4-({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-amino)-benzoic acid ethyl ester

LRMS: 437.

Example 52

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-piperidin-1-yl-methanone

LRMS: 357.

Example 53

Methyl-(4-methyl-5'-nitro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3-yl)-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-amine

LRMS: 368.

Example 54

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (3-fluoro-phenyl)-amide

LRMS: 383.

Example 55

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (2,4-difluoro-phenyl)-amide

LRMS: 401.

Example 56

Methyl-[4-methyl-1-(pyrrolidin-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 379.

Example 57

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (3-methoxy-phenyl)-amide

LRMS: 395.

Example 58

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (3-nitro-phenyl)-amide

LRMS: 410.

Example 59

1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-pyrrolidine-2-carboxylic acid methyl ester

LRMS: 401.

Example 60

Methyl-[4-methyl-1-(5-nitro-thiazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 374.

Example 61

Methyl ester 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrahydro-2H-[1,2'] bipyridinyl-5'-carboxylic acids

LRMS: 381.

Example 62

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl -5'-yl}-methanol

LRMS: 353.

Example 63

Methyl-[4-methyl-1-(piperidin-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 393.

Example 64

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (3-cyano-phenyl)-amide

LRMS: 390.

Example 65

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (3,4-difluoro-phenyl)-amide

LRMS: 401.

Example 66

Methyl-[4-methyl-1-(morpholine-4-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 395.

Example 67

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-chloro-phenyl)-amide

LRMS: 399.

Example 68

Methyl-[4-methyl-1-(6-methyl-pyridazin-3-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 338.

Example 69

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-cyano-phenyl)-amide

LRMS: 390.

Example 70

4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid biphenyl-4-ylamide

LRMS: 441.

Example 71

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-trifluoromethyl-phenyl)-amide

LRMS: 433.

Example 72

Methyl-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-sulfonyl}-ethyl)-carbamic acid benzyl ester

LRMS: 501.

Example 73

Cyclopropyl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone

LRMS: 314.

Example 74

Cyclobutyl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone

LRMS: 328.

Example 75

Methyl-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-sulfonyl}-ethyl)-amide tetrahydrofuran -3-carboxylic acids

LRMS: 465.

Example 76

Cyclohexanecarboxylic acid methyl-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-sulfonyl}-ethyl)-amide

LRMS: 477.

Example 77

(5,7-dichloro-1H-indol-2-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1 -yl}-methanone

LRMS: 458.

Example 78

4-({4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-amino)-benzoic acid

LRMS: 409.

Example 79

(1-Benzoxazol-2-yl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 363.

Example 80

(1H-indol-2-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone

LRMS: 389.

Example 81

(5-fluoro-1H-indol-2-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl }-methanone

LRMS: 407.

Example 82

(5-Methoxy-3-methyl-benzofuran-2-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1 -yl}-methanone

LRMS: 434.

Example 83

(5-chloro-benzofuran-2-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- methanone

LRMS: 424.

Example 84

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}(5-nitro-benzofuran-2-yl)- methanone

LRMS: 435.

Example 85

(5-chloro-2,3-dihydro-benzofuran-2-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine -1-yl}-methanone

LRMS: 426.

Example 86

(4-hydroxy-piperidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- methanone

LRMS: 373.

Example 87

1-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-carbonyl}-benzofuran-5-yl)- ethanone

LRMS: 432.

Example 88

1-(3-methyl-2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-1H-indole -5-yl)-ethanone

LRMS: 445.

Example 89

[1-(5-chloro-benzothiazol-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 413.

Example 90

tert-butyl ester (3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-3-aza-bicyclo [3.1.0]hex-6-yl)carbamic acids

LRMS: 470.

Example 91

3-(4-chloro-phenoxy)-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- propan-1-one

LRMS: 428.

Example 92

Pyridin-2-ylamide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid

LRMS: 366.

Example 93

1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-piperidine-4-carboxylic acid amide hydrochloride

LRMS: 436.

Example 94

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (5-chloro-pyridin-2-yl)-amide

LRMS: 400.

Example 95

3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-cyclopentanone

LRMS: 356.

Example 96

(3-hydroxy-cyclopentyl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone

LRMS: 358.

Example 97

4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-cyclohexanone

LRMS: 370.

Example 98

3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-cyclohexanone

LRMS: 370.

Example 99

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (5-nitro-pyridin-2-yl)-amide

LRMS: 413.

Example 100

[4-({4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-amino)-phenyl]-acetic acid

LRMS: 423.

Example 101

(4-amino-piperidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- methanone hydrochloride

LRMS: 408.

Example 102

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (6-methyl-pyridin-2-yl)-amide

LRMS: 380.

Example 103

1-methyl-4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-carbonyl}-pyrrolidin-2-one

LRMS: 371.

Example 104

1-benzyl-3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-pyrrolidin-2-one

LRMS: 447.

Example 105

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (5-trifluoromethyl-pyridin-2-yl)-amide

LRMS: 434.

Example 106

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-cyclohexanecarboxylic acid (4-cyano-phenyl)-amide

LRMS: 389.

Example 107

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-carbamoyl-phenyl)-amide

LRMS: 408.

Example 108

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-sulfamoyl-phenyl)-amide

LRMS: 444.

Example 109

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (5-methyl-thiazol-2-yl)-amide

LRMS: 386.

Example 110

(5,6-dichloro-benzothiazol-2-yl)-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid

LRMS: 491.

Example 111

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-methyl-thiazol-2-yl)-amide

LRMS: 386.

Example 112

Azetidin-1-yl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone hydrochloride

LRMS: 365.

Example 113

Ethyl ester [2-({4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-amino)-thiazole-4 -yl]-acetic acid

LRMS: 458.

Example 114

(4,5-dimethyl-thiazol-2-yl)-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid

LRMS: 400.

Example 115

[2-({4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-carbonyl}-amino)-thiazol-4-yl ]-acetic acid

LRMS: 430.

Example 116

Benzothiazol-2-ylamide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid

LRMS: 422.

Example 117

Thiazol-2-ylamide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid

LRMS: 372.

Example 118

[6-(2-dimethylamino-ethylamino)-pyridin-3-yl]-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine -1-carboxylic acids

LRMS: 452.

Example 119

N-(4-chloro-phenyl)-2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- acetamide

LRMS: 413.

Example 120

N,N-dimethyl-2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-acetamide

LRMS: 331.

Example 121

[6-(2-pyrrolidin-1-yl-ethylamino)-pyridin-3-yl]-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- amino]-piperidine-1-carboxylic acids

LRMS: 478.

Example 122

tert-butyl ester {2-[5-({4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-amino )-pyridin-2-yloxy]-ethyl}-carbamic acid

LRMS: 525.

Example 123

[6-(2-amino-ethoxy)-pyridin-3-yl]-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin -1-carboxylic acids

LRMS: 425.

Example 124

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-methylsulfamoyl-phenyl)-amide

LRMS: 458.

Example 125

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-methanesulfonyl-phenyl)-amide

LRMS: 443.

Example 126

(5-methyl-[1,3,4]thiadiazol-2-yl)-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]- piperidine-1-carboxylic acids

LRMS: 387.

Example 127

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-methylsulfamoyl-phenyl)-amide hydrochloride

LRMS: 495.

Example 128

Methyl-[4-methyl-1-(1-phenyl-ethyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 350.

Example 129

(3-hydroxy-pyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- methanone

LRMS: 359.

Example 130

4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester

LRMS: 346.

Example 131

[4-(2-dimethylamino-ethyl)-thiazol-2-yl]-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine -1-carboxylic acids

LRMS: 443.

Example 132

4-methanesulfonyl-benzylamide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid

LRMS: 457.

Example 133

4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-acetylsulfamoyl-phenyl)-amide

LRMS: 486.

Example 134

1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-phenyl-ethane-1,2- part

LRMS: 378.

Example 135

Methyl-[4-methyl-1-(6-methylamino-pyrimidin-4-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 353.

Example 136

Methyl-[4-methyl-1-(6-pyrrolidin-1-yl-pyrimidin-4-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- Amen

LRMS: 393.

Example 137

[1-(6-benzylamino-pyrimidin-4-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 429.

Example 138

N,N-dimethyl-N'-(6-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- pyrimidine-4-yl)-ethane-1,2-diamine

LRMS: 410.

Example 139

[1-(6-chloro-pyrimidin-4-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 358.

Example 140

[1-(2-fluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 354.

Example 141

[1-(2-chloro-pyrimidin-4-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 359.

Example 142

[1-(4-chloro-pyrimidin-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 359.

Example 143

Methyl-[4-methyl-1-(2-methylamino-pyrimidin-4-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 353.

Example 144

Methyl-[4-methyl-1-(4-pyrrolidin-1-yl-pyrimidin-2-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- Amen

LRMS: 353.

Example 145

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (3-methyl-isoxazol-5-yl)-amide

LRMS: 370.

Example 146

(3-methyl-isoxazol-4-yl)-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acids

LRMS: 370.

Example 147

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (5-methyl-isoxazol-3-yl)-amide

LRMS: 370.

Example 148

(5-tert-butyl-isoxazol-3-yl)-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid

LRMS: 412.

Example 149

Isoxazol-3-ylamide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid

LRMS: 356.

Example 150

N-methyl-3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propionamide

LRMS: 331.

Example 151

1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-2-one

LRMS: 302.

Example 152

{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-oxo-acetic acid methyl ester

LRMS: 332.

Example 153

(1-cyclohexylmethyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 342.

Example 154

[1-(5-amino-thiazol-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 344.

Example 155

Methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 246.

Example 156

3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionic acid methyl ester

LRMS: 346.

Example 157

(1-benzenesulfonylmethyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 400.

Example 158

(3-hydroxy-pyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- methanone

LRMS: 359.

Example 159

1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propane-1,2-dione

LRMS: 316.

Example 160

4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (6-sulfamoyl-pyridin-3-yl)-amide

LRMS: 445.

Example 161

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (6-acetylamino-pyridin-3-yl)-amide

LRMS: 423.

Example 162

[4-(2-dimethylamino-ethylsulfamoyl)-phenyl]-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid

LRMS: 515.

Example 163

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (6-cyano-pyridin-3-yl)-amide

LRMS: 391.

Example 164

Pyridin-2-ylamide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrahydro-2H-[1, 2']bipyridinyl-5'-sulfo acids

LRMS: 479.

Example 165

[6-(Pyrrolidin-1-carbonyl)-pyridin-3-yl]-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine -1-carboxylic acids

LRMS: 463.

Example 166

2-imidazol-1-yl-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone

LRMS: 354.

Example 167

Methylamide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl -5'-carboxylic acids

LRMS: 380.

Example 168

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl -5'-yl}-morpholin-4-yl-methanone

LRMS: 436.

Example 169

Propylamide 5-({4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-amino)-pyridine-2-carboxylic acid

LRMS: 451.

Example 170

Amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl -5'-carboxylic acids

LRMS: 366.

Example 171

4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl- 5'-carbonitrile

LRMS: 348.

Example 172

[4-(pyrrolidin-1-sulfonyl)-phenyl]-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid

LRMS: 498.

Example 173

[4-(morpholine-4-sulfonyl)-phenyl]-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid

LRMS: 514.

Example 174

(3-hydroxy-pyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- methanone

LRMS: 359.

Example 175

[6-(morpholine-4-carbonyl)-pyridin-3-yl]-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine -1-carboxylic acids

LRMS: 479.

Example 176

[6-(morpholine-4-carbonyl)-pyridin-3-yl]-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine -1-carboxylic acids

LRMS: 479.

Example 177

2-imidazol-1-yl-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone

LRMS: 354.

Example 178

Isoxazol-3-ylamide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid

LRMS: 356.

Example 179

(2,5-dimethyl-2H-pyrazol-3-yl)-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1 -carboxylic acids

LRMS: 383.

Example 180

(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine -1-carboxylic acids

LRMS: 409.

Example 181

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (3-methyl-isothiazol-5-yl)-amide

LRMS: 386.

Example 182

4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-ylmethyl}-benzoic acid

LRMS: 380.

Example 183

Methyl-[4-methyl-5'-(pyrrolidine-1-sulfonyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3-yl]-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-amine

LRMS: 456.

Example 184

Methylamide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl -5'-sulfo acids

LRMS: 416.

Example 185

4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-ylmethyl}-benzenesulfonamide

LRMS: 415.

Example 186

N-tert-butyl-4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-ylmethyl}-benzenesulfonamide

LRMS: 472.

Example 187

1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-pyrazol-1-yl-ethanone

LRMS: 354.

Example 188

Methyl-[4-methyl-1-(5-nitro-benzoxazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 408.

Example 189

(2-hydroxy-ethyl)-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrahydro-2H -[1,2']bipyridinyl-5'-sulfo acid

LRMS: 446.

Example 190

N-tert-butyl-4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-ylmethyl}-benzenesulfonamide

LRMS: 471.

Example 191

N-methyl-2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-oxo-acetamide

LRMS: 331.

Example 192

[1-(5-ethanesulfonyl-benzoxazol-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 455.

Example 193

Methyl-[4-methyl-1-(5-methyl-benzoxazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 377.

Example 194

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (6-chloro-pyridin-3-yl)-amide

LRMS: 400.

Example 195

Methyl-(4-methyl-1-quinolin-2-yl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 373.

Example 196

Amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl -5'-sulfo acids

LRMS: 402.

Example 197

1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-pyrrolidin-1-yl-ethan- 1,2-dione

LRMS: 371.

Example 198

Methyl-[4-methyl-1-(4-methyl-benzoxazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 377.

Example 199

1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-morpholin-4-yl-ethan- 1,2-dione

LRMS: 387.

Example 200

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (6-methanesulfonyl-pyridin-3-yl)-amide

LRMS: 444.

Example 201

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (6-methanesulfonyl-pyridin-3-yl)-amide

LRMS: 444.

Example 202

Methyl-[4-methyl-1-(6-nitro-benzoxazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 408.

Example 203

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (6-methanesulfonyl-pyridin-3-yl)-amide

LRMS: 444.

Example 204

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (6-methanesulfonyl-pyridin-3-yl)-amide

LRMS: 444.

Example 205

Methyl-[4-methyl-1-(6-nitro-benzoxazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 408.

Example 206

Methyl-[4-methyl-1-(toluene-3-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 400.

Example 207

Methyl-[4-methyl-1-(4-trifluoromethyl-benzenesulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 454.

Example 208

(1-benzothiazol-2-yl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino

LRMS: 379.

Example 209

[1-(5,7-dimethyl-benzoxazol-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 391.

Example 210

2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-benzoxazole-6-carboxylic acid methyl ester

LRMS: 421.

Example 211

Methyl-[4-methyl-1-(6-methyl-benzoxazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 377.

Example 212

[1-(6-Methoxy-benzoxazol-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 393.

Example 213

Methyl-[4-methyl-1-(5-trifluoromethyl-benzothiazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 447.

Example 214

[1-(5,7-dichloro-benzoxazol-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 432.

Example 215

[1-(6-chloro-pyridin-3-sulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 422.

Example 216

[1-(4-chloro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 421.

Example 217

[1-(4-Fluoro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 404.

Example 218

4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-benzonitrile

LRMS: 411.

Example 219

4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-benzenesulfonyl fluoride

LRMS: 468.

Example 220

2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-benzonitrile

LRMS: 411.

Example 221

1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-tetrazol-1-yl-ethanone

LRMS: 356.

Example 222

Methyl-[4-methyl-1-(2,2,2-trifluoroethanesulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 392.

Example 223

[1-(2,6-difluoro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 422.

Example 224

[1-(4-tert-butyl-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 442.

Example 225

[1-(2,4-difluoro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 422.

Example 226

Methyl-[4-methyl-1-(2-trifluoromethyl-benzenesulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 454.

Example 227

[1-(3,5-bis-trifluoromethyl-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 522.

Example 228

[1-(3,5-dichloro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 455.

Example 229

4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-benzoic acid

LRMS: 431.

Example 230

[1-(6-chloro-pyridin-3-sulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 422.

Example 231

[1-(4-chloro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 421.

Example 232

[1-(4-Fluoro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 404.

Example 233

4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-benzonitrile

LRMS: 411.

Example 234

4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-benzenesulfonyl fluoride

LRMS: 468.

Example 235

2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-benzonitrile

LRMS: 411.

Example 236

1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-tetrazol-1-yl-ethanone

LRMS: 356.

Example 237

Methyl-[4-methyl-1-(2,2,2-trifluoroethanesulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 392.

Example 238

[1-(2,6-difluoro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 422.

Example 239

[1-(4-tert-butyl-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 442.

Example 240

[1-(2,4-difluoro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 422.

Example 241

Methyl-[4-methyl-1-(2-trifluoromethyl-benzenesulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 454.

Example 242

[1-(3,5-bis-trifluoromethyl-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 522.

Example 243

[1-(3,5-dichloro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 455.

Example 244

4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-benzoic acid

LRMS: 431.

Example 245

(3-fluoro-phenyl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone

LRMS: 368.

Example 246

Isothiazol-4-yl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone

LRMS: 357.

Example 247

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-thiophen-3-yl-methanone

LRMS: 356.

Example 248

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}(5-methyl-1H-pyrazol-3-yl )-methanone

LRMS: 354.

Example 249

(5-methyl-isoxazol-3-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- methanone

LRMS: 355.

Example 250

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}(5-methyl-thiophen-2-yl)- methanone

LRMS: 371.

Example 251

(4-fluoro-phenyl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone

LRMS: 368.

Example 252

Methyl-[4-methyl-1-(3-nitro-benzenesulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 431.

Example 253

[1-(3-Fluoro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 404.

Example 254

(2-fluoro-phenyl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone

LRMS: 368.

Example 255

(1,5-dimethyl-1H-pyrazol-3-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1 -yl}-methanone

LRMS: 368.

Example 256

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}(2-methyl-thiazol-4-yl)- methanone

LRMS: 371.

Example 257

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-thiazol-4-yl-methanone

LRMS: 357.

Example 258

(4-methyl-isothiazol-5-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- methanone

LRMS: 371.

Example 259

2,2-dimethyl-5-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2 -oxo-ethyl)-[1,3]dioxolan-4-one

LRMS: 403.

Example 260

2-cyclopropyl-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)- acetamide

LRMS: 436.

Example 261

N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-sulfonyl}-ethyl)-methanesulfonamide

LRMS: 432.

Example 262

(3-hydroxy-pyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- methanone

LRMS: 359.

Example 263

4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-ylmethyl}-benzonitrile

LRMS: 362.

Example 264

3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-benzenesulfonyl fluoride

LRMS: 469.

Example 265

2,2-dimethyl-5-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2 -oxo-ethyl-[1,3]dioxolan-4-one

LRMS: 402.

Example 266

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid benzyl ester

LRMS: 381.

Example 267

4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-ylmethyl}-benzenesulfonamide

LRMS: 416.

Example 268

[1-(1H-imidazol-2-ylmethyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 326.

Example 269

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid 2-chloro-benzyl ester

LRMS: 415.

Example 270

Methyl-[4-methyl-1-(1-methyl-1H-imidazol-2-ylmethyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 340.

Example 271

1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-phenoxy-ethanone

LRMS: 380.

Example 272

2-(4-fluoro-phenoxy)-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- ethanone

LRMS: 381.

Example 273

4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid 2,2,2-trichloroethyl ester

LRMS: 420.

Example 274

2-(2-chloro-phenoxy)-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- ethanone

LRMS: 415.

Example 275

2-(3-chloro-phenoxy)-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- ethanone

LRMS: 415.

Example 276

2-methanesulfonyl-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone

LRMS: 367.

Example 277

2-(1,1-dioxo-tetrahydro-1%6N-thiophen-3-yl)-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4 -yl)-amino]-piperidin-1-yl}-ethanone

LRMS: 407.

Example 278

Methyl-[4-methyl-1-(1-phenyl-ethyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 351.

Example 279

1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-(toluene-4-sulfonyl)- ethanone

LRMS: 443.

Example 280

4-hydroxy-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone

LRMS: 304.

Example 281

1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-nitro-propan-1-one

LRMS: 347.

Example 282

5-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-oxo-ethyl)- thiazolidine-2,4-dione

LRMS: 404.

Example 283

3-hydroxy-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one

LRMS: 318.

Example 284

N-(4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-4-oxo-butyl)- methanesulfonamide

LRMS: 410.

Example 285

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid 2,2-dimethyl-propyl ester

LRMS: 360.

Example 286

1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-(thiazolidine-3-sulfonyl)- ethanone

LRMS: 440.

Example 287

(3,4-dihydroxy-pyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl }-methanone

LRMS: 376.

Example 288

4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-carbonyl}-thiazolidin-2-one

LRMS: 376.

Example 289

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid prop-2-inyl ester

LRMS: 328.

Example 290

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (2-cyano-ethyl)-amide

LRMS: 342.

Example 291

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (2-cyano-ethyl)-amide

LRMS: 342.

Example 292

1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-cyclohexyl}-ethanone oxime

LRMS: 302.

Example 293

Cyanomethyl-methyl-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid

LRMS: 342.

Example 294

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid isopropyl ester

LRMS: 332.

Example 295

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (2-cyano-ethyl)-methyl-amide

LRMS: 356.

Example 296

4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-ylmethyl}-pyridin-1-ol

LRMS: 355.

Example 297

{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-acetonitrile

LRMS: 285.

Example 298

[1-(2-fluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

Procedure J

154 ul (mmol?) of 2-fluoro-benzaldehyde is added to a solution of the product from Procedure H (50 mg, mmol?) dissolved in 5 ml of methanol. The resulting mixture is stirred at room temperature for 4 hours, after which x mg (y mmol) of sodium cyanoborohydride is added, and the resulting mixture is stirred at room temperature for 18 hours. The reaction was quenched by adding 2 drops of 1N NaOH (aq), and the mixture was concentrated under reduced pressure to remove methanol. The residue is dissolved in chloroform and washed with water. The aqueous layer is washed again three times with chloroform, after which the combined organic extracts are dried over MgSO4 and concentrated to dryness under vacuum. The crude product was then purified by flash chromatography (silica; 2.5% methanol in chloroform) to give 36 mg (47.5%) of the title compound as a white solid.

LRMS: 372.4 (M+1).

The title compounds for Examples 299-324 were obtained by a procedure analogous to that described in Example 298.

Example 299

(1-benzyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 336.

Example 300

(1-furan-2-ylmethyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 326.

Example 301

[1-(4-Methoxy-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 366.

Example 302

[1-(4-fluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 354.

Example 303

Methyl-(4-methyl-1-pyridin-3-ylmethyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 337.

Example 304

Methyl-(4-methyl-1-thiazol-2-ylmethyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 343.

Example 305

Methyl-(4-methyl-1-pyridin-2-ylmethyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 337.

Example 306

Methyl-[4-methyl-1-(1-phenyl-ethyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 350.

Example 307

(1-benzyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 336.

Example 308

(1-benzyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 336.

Example 309

3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-ylmethyl}-benzonitrile

LRMS: 361.

Example 310

[1-(3-fluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 354.

Example 311

[1-(3-methoxy-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 366.

Example 312

3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-ylmethyl}-benzoic acid

LRMS: 380.

Example 313

[1-(2-fluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 354.

Example 314

[1-(2,6-difluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 372.

Example 315

Methyl-(4-methyl-1-phenethyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 350.

Example 316

[1-(2,3-difluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 372.

Example 317

[1-(3,4-difluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 372.

Example 318

[1-(4-methanesulfonyl-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 414.

Example 319

Methyl-{4-methyl-1-[4-(piperidin-1-sulfonyl)-benzyl]-piperidin-3-yl}(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 483.

Example 320

[1-(3,5-difluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 372.

Example 321

[1-(3-chloro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 371.

Example 322

[1-(3,5-difluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 372.

Example 323

[1-(3-chloro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 371.

Example 324

[1-(3,5-dichloro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

LRMS: 405.

Claims (27)

1. Compound formula [image] , or a pharmaceutically acceptable salt thereof; indicated by what R1 is a group of the formula [image] , where y is 0, 1 or 2; R4 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C2-C6)alkenyl, (C2-C6)alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with deuterium , hydroxy, amino, trifluoromethyl, (C1-C4)alkoxy, (C1-C6)acyloxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, cyano, nitro, (C2-C6)alkenyl, ( C2-C6)alkynyl or (C1-C6)acylamino; or R4 is (C3-C10)cycloalkyl, wherein the cycloalkyl group is optionally substituted with deuterium, hydroxy, amino, trifluoromethyl, (C1-C6)acyloxy, (C1-C6)acylamino, (C1-C6)alkylamino, ((C1 -C6)alkyl)2amino, cyano, cyano(C1-C6)alkyl, trifluoromethyl(C1-C6)alkyl, nitro, nitro(C1-C6)alkyl or (C1-C6)acylamino; R 5 is (C 2 -C 9 )heterocycloalkyl, wherein the heterocycloalkyl groups must be substituted with one to five groups consisting of carboxy, cyano, amino, deuterium, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo, ( C1-C6)acyl, (C1-C6)alkylamino, amio(C1-C6)alkyl, (C1-C6)alkoxy-CO-NH, (C1-C6)alkylamino-CO-, (C2-C6)alkenyl, ( C2-C6)alkynyl, (C1-C6)alkylamino, amino(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)acyloxy(C1 -C6)alkyl, nitro, cyano(C1-C6)alkyl, halo(C1-C6)alkyl, nitro(C1-C6)alkyl, trifluoromethyl, trifluoromethyl(C1-C6)alkyl, (C1-C6)acylamino, (C1 -C6)acylamino(C1-C6)alkyl, (C1-C6) alkoxy(C1-C6)acylamino, amino(C1-C6)acyl, amino(C1-C6)acyl(C1-C6)alkyl, (C1-C6 )alkylamino(C1-C6)acyl, ((C1-C6)alkyl)2amino(C1-C6)acyl, R15R16N-CO-O-, R15R16N-CO-(C1-C6)alkyl, (C1-C6)alkyl- S(O)m, R15R16NS(O)m, R15R16NS(O)m(C1-C6)alkyl, R15S(O)mR16N, R15S(O)mR16N(C1-C6)alkyl, where m is 0, 1 or 2 , and R 15 and R 16 are each independently selected from hydrogen or (C 1 -C 6 )alkyl; and formula group [image] , where a is 0, 1, 2, 3 or 4; b, c, e, f and g are each independently 0 or 1; d is 0, 1, 2, or 3; X is S(O)n, where n is 0, 1 or 2; oxygen, carbonyl or -C(=N-cyano)-; Y is S(O)n, where n is 0, 1 or 2; or carbonyl; and Z is carbonyl, C(O)O-, C(O)NR-, where R is hydrogen or (C1-C6)alkyl; or Z is S(O)n, where n is 0, 1 or 2; R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of hydrogen or (C 1 -C 6 )alkyl optionally substituted with deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 6 )acyloxy, (C 1 -C 6 ) acylamino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, cyano, cyano(C1-C6)alkyl, trifluoromethyl(C1-C6)alkyl, nitro, nitro(C1-C6)alkyl or (C1- C6)acylamino; R12 is (C6-C10)aryl, (C2-C9)heteroaryl, (C3-C10)cycloalkyl or (C2-C9)heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are optionally substituted with one to four groups forming hydrogen, deuterium, amino, halo, oxo, hydroxy, nitro, carboxy, (C2-C6)alkenyl, (C2-C6)alkynyl, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkosky, (C3 -C10)Cycloalkyl, (C1-C6)alkyl-CO-NH-, (C1-C6)Alkoxy-CO-NH-, (C1-C6)Alkyl-CO-NH-(C1-C6)Alkyl, (C1- C6)Alkoxy-CO-NH-(C1-C6)Alkyl, (C1-C6)Alkoxy-CO-NH-(C1-C6)Alkoxy, Carboxy, Carboxy(C1-C6)Alkyl, Carboxy(C1-C6)Alkoxy , Benzyloxycarbonyl(C1-C6)Alkoxy, (C1-C6)Alkoxycarbonyl(C1-C6)Alkoxy, (C6-C10)Aryl, Amino, Amino(C1-C6)Alkyl, (C1-C6)Alkoxycarbonylamino, (C6-C10 )aryl(C1-C6)Alkoxycarbonylamino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkyl)2amino(C1 -C6)alkyl, Hydroxy, (C1-C6)Alkoxy, Carboxy, Carboxy(C1-C6)Alkyl, (C1-C6)Alkoxycarbonyl, (C1-C6)Alkoxycarbonyl(C1-C6) Alkyl, (C1-C6)Alkoxy-CO-NH-, (C1-C6)Alkyl-CO-NH-, Cyano, (C5-C9)Heterocycloalkyl, Amino-CO-NH-, (C1-C6)Alkylamino-CO -NH-, ((C1-C6)alkyl)2amino-CO-NH-, (C6-C10)arylamino-CO-NH-, (C5-C9)heteroarylamino-CO-NH-, (C1-C6)alkylamino- CO-NH-(C1-C6)alkyl, ((C1-C6)alkyl)2amino-CO-NH-(C1-C6)alkyl, (C6-C10)arylamino-CO-NH-(C1-C6)alkyl, (C5-C9)Heteroarylamino-CO-NH-(C1-C6)Alkyl, (C1-C6)Alkylcyano, (C1-C6)Alkylcarboxy(C1-C6)Alkoxy, (C1-C6)Alkylcarboxy, Sulfonylamino, Aminosulfonyl, Sulfonylamino (C1-C6)alkyl, sulfonylaminocarboxy(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C6-C10)arylsulfonyl, ( C6-C10)arylsulfonylamino, (C6-C10)arylsulfonylamino(C1-C6)alkyl, (C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C3-C10)cycloalkyl, (C3-C10 )cycloalkoxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C6-C10)arylamino, (C1-C6)alkylthio, (C6-C10)arylthio, (C1-C6)alkylsulfinyl, (C6 -C10)arylsulfinyl, (C1-C6)alkylsulfonyl, (C6-C10)arylsulf onyl, (C1-C6)acyl, (C1-C6)alkoxy-CO-NH-, (C1-C6)alkylamino-CO-, (C5-C9)heteroaryl, (C2-C9)heterocycloalkyl or (C6-C10) aryl, wherein the heteroaryl, heterocycloalkyl and aryl groups optionally substituted at R12 may be further substituted with one to three halo groups, (C1-C6)alkyl, (C1-C6)alkyl-CO-NH-, (C1 -C6)Alkoxy-CO-NH-, (C1-C6)Alkyl-CO-NH-(C1-C6)Alkyl, (C1-C6)Alkoxy-CO-NH-(C1-C6)Alkyl, (C1-C6 )Alkoxy-CO-NH-(C1-C6)Alkoxy, Carboxy, Carboxy(C1-C6)Alkyl, Carboxy(C1-C6)Alkoxy, Benzyloxycarbonyl(C1-C6)Alkoxy, (C1-C6)Alkoxycarbonyl(C1-C6 )Alkoxy, (C6-C10)Aryl, Amino, Amino(C1-C6)Alkyl, (C1-C6)Alkoxycarbonylamino, (C6-C10)Aryl(C1-C6)Alkoxycarbonylamino, (C1-C6)Alkylamino, ((C1 -C6)alkyl)2amino, (C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkyl)2amino(C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, carboxy, carboxy(C1 -C6)alkyl, (C1-C6)Alkoxycarbonyl, (C1-C6)Alkoxycarbonyl(C1-C6)Alkyl, (C1-C6)Alkoxy-CO-NH-, (C1-C6)Alkyl-CO-NH-, cyano , (C5-C9)heterocycloalkyl, amino-CO-N H-, (C1-C6)alkylamino-CO-NH-, ((C1-C6)alkyl)2amino-CO-NH-, (C6-C10)arylamino-CO-NH-, (C5-C9)heteroarylamino-CO -NH-, (C1-C6)alkylamino-CO-NH-(C1-C6)alkyl, ((C1-C6)alkyl)2amino-CO-NH-(C1-C6)alkyl, (C6-C10)arylamino- CO-NH-(C1-C6)alkyl, (C5-C9)heteroarylamino-CO-NH-(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino( C1-C6)alkyl, (C6-C10)arylsulfonyl, (C6-C10)arylsulfonylamino, (C6-C10)arylsulfonylamino(C1-C6)alkyl, (C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6 )alkyl, (C5-C9)heteroaryl and (C2-C9)heterocycloalkyl; R2 and R3 are each independently selected from the group consisting of hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, (C2-C6)alkenyl, (C2-C6)alkynyl, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)Alkoxy, (C3-C10)cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl groups are optionally substituted with one to three groups selected from halo, hydroxy, carboxy, amino(C1-C6)alkylthio, (C1-C6 )alkylamino, ((C1-C6)alkyl)2amino, (C5-C9)heteroaryl, (C2-C9)heterocycloalkyl, (C3-C9)cycloalkyl or (C6-C10)aryl; or R 2 and R 3 are each independently (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkoxy, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl)2amino, (C 6 -C 10 )arylamino, (C 1 -C 6 ) alkylthio, (C6-C10)arylthio, (C1-C6)alkylsulfinyl, (C6-C10)arylsulfinyl, (C1-C6)alkylsulfonyl, (C6-C10)arylsulfonyl, (C1-C6)acyl, (C1-C6)alkoxy -CO-NH-, (C1-C6)alkylamino-CO-, (C5-C9)heteroaryl, (C2-C9)heterocycloalkyl or (C6-C10)aryl, wherein the heteroaryl, heterocycloalkyl and aryl groups are optionally substituted with one up to three of halo, (C1-C6)alkyl, (C1-C6)alkyl-CO-NH-, (C1-C6)alkoxy-CO-NH-, (C1-C6)alkyl-CO-NH-(C1- C6)alkyl, (C1-C6)Alkoxy-CO-NH-(C1-C6)Alkyl, (C1-C6)Alkoxy-CO-NH-(C1-C6)Alkoxy, Carboxy, Carboxy(C1-C6)Alkyl, Carboxy(C1-C6)Alkoxy, Benzyloxycarbonyl(C1-C6)Alkoxy, (C1-C6)Alkoxycarbonyl(C1-C6)Alkoxy, (C6-C10)Aryl, Amino, Amino(C1-C6)Alkyl, (C1-C6 )Alkoxycarbonylamino, (C6-C10)aryl(C1-C6)Alkoxycarbonylamino, (C1-C6)Alkylamino, ((C1-C6)Alkyl)2amino, (C1-C6)Alkylamino(C1-C6)Alkyl, ((C1- C6)alkyl)2amino(C1-C6)alkyl, hydroxy, ( C1-C6)Alkoxy, Carboxy, Carboxy(C1-C6)Alkyl, (C1-C6)Alkoxycarbonyl, (C1-C6)Alkoxycarbonyl(C1-C6)Alkyl, (C1-C6)Alkoxy-CO-NH-, (C1 -C6)alkyl-CO-NH-, cyano, (C5-C9)heterocycloalkyl, amino-CO-NH-, (C1-C6)alkylamino-CO-NH-, ((C1-C6)alkyl)2amino-CO- NH-, (C6-C10)arylamino-CO-NH-, (C5-C9)heteroarylamino-CO-NH-, (C1-C6)alkylamino-CO-NH-(C1-C6)alkyl, ((C1-C6 )alkyl)2amino-CO-NH-(C1-C6)alkyl, (C6-C10)arylamino-CO-NH-(C1-C6)alkyl, (C5-C9)heteroarylamino-CO-NH-(C1-C6) alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C6-C10)arylsulfonyl, (C6-C10)arylsulfonylamino, (C6-C10)arylsulfonylamino( C1-C6)alkyl, (C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C5-C9)heteroaryl or (C2-C9)heterocycloalkyl; with the proviso that R 5 must be substituted with a group of formula II. 2. A compound according to claim 1, characterized in that R5 is (C2-C9)heterocycloalkyl optionally substituted with one to three groups selected from deuterium, hydroxy, (C1-C6)alkyl, halo, (C1-C6)alkoxy and groups of the formula II. 3. Compound according to claim 1, characterized in that a is 0; b is 1; X is carbonyl; c is 0; d is 0; e is 0; f is 0; and g is 0. 4. Compound according to claim 1, characterized in that a is 0; b is 1; X is carbonyl; c is 0; d is 1; e is 0; f is 0; and g is 0. 5. Compound according to claim 1, characterized in that a is 0; b is 1; X is carbonyl; c is 1; d is 0; e is 0; f is 0; and g is 0. 6. Compound according to claim 1, characterized in that a is 0; b is 1; X is -C(=N=cyano)-; c is 1; d is 0; e is 0; f is 0; and g is 0. 7. Compound according to claim 1, characterized in that a is 0; b is 0; c is 0; d is 0; e is 0; f is 0; g is 1; and Z is -C(O)-O-. 8. Compound according to claim 1, characterized in that a is 0; b is 1; X is S(O)n; n is 2; c is 0; d is 0; e is 0; f is 0; and g is 0. 9. Compound according to claim 1, characterized in that a is 0; b is 1; X is S(O)n; n is 2; c is 0; d is 2; e is 0; f is 1; g is 1; and Z is carbonyl. 10. Compound according to claim 1, characterized in that a is 0; b is 1; X is S(O)n; n is 2; c is 0; d is 2; e is 0; f is 1; and g is 0. 11. Compound according to claim 1, characterized in that a is 0; b is 1; X is carbonyl; c is 1; d is 0; e is 1; Y is S(O)n; n is 2; f is 0; and g is 0. 12. Compound according to claim 1, characterized in that a is 0; b is 1; X is S(O)n; n is 2; c is 1; d is 0; e is 0; f is 0; and g is 0. 13. Compound according to claim 1, characterized in that a is 1; b is 1; X is carbonyl; c is 1; d is 0; e is 0; f is 0; and g is 0. 14. Compound according to claim 1, characterized in that a is 0; b is 1; X is S(O)n; c is 0; d is 1; e is 1; Y is S(O)n; n is 2; f is 0; and g is 0. 15. Compound according to claim 1, characterized in that a is 0; b is 1; X is S(O)n; c is 0; d is 2, 3 or 4; e is 1; Y is S(O)n; n is 2; f is 1; and g is 0. 16. Compound according to claim 1, characterized in that a is 0; b is 1; X is oxygen; c is 0; d is 2, 3 or 4; e is 1; Y is S(O)n; n is 2; f is 1; and g is 0. 17. Compound according to claim 1, characterized in that a is 0; b is 1; X is oxygen; c is 0; d is 2, 3 or 4; e is 1; Y is S(O)n; n is 2; f is 0; and g is 0. 18. Compound according to claim 1, characterized in that a is 0; b is 1; X is carbonyl; c is 1; d is 2, 3 or 4; e is 1; Y is S(O)n; f is 0; and g is 0. 19. Compound according to claim 1, characterized in that a is 0; b is 1; X is carbonyl; c is 1; d is 2, 3 or 4; e is 1; Y is S(O)n; n is 2; f is 1; and g is 0. 20. Compound according to patent claim 1, characterized in that R12 is (C6-C10)aryl or (C2-C9)heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with one to four groups consisting of hydrogen, halo, hydroxy, carboxy , trifluoromethyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-CO-NH-, amino, amino(C1-C6)alkyl, (C1-C6)alkylamino, ((C1- C6)alkyl)2amino, cyano, amino-CO-NH-, (C1-C6)alkylamino-CO-NH-, ((C1-C6)alkyl)2-CO-NH-, (C5-C9)heteroarylamino-CO -NH-, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylsulfonylamino, (C 6 -C 10 )arylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino and (C 1 -C 6 )alkoxy-CO-NH-. 21. Compound according to patent claim 1, characterized in that said compound is selected from the group consisting of: 4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-ylmethyl}-benzenesulfonamide; 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-sulfamoyl-phenyl)-amide; 4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-nitro-phenyl)-amide; 1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-tetrazol-1-yl-ethanone; 4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-methylsulfamoyl-phenyl)-amide; (3-hydroxy-pyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- methanone; [2-({4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-carbonyl}-amino)-thiazol-4-yl ]-acetic acid; Methyl-(4-methyl-5'-nitro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3-yl)-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-amine; 5-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-oxo-ethyl)- thiazolidine-2,4-dione; {4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-thiazolidin-3-yl-methanone; Methyl-[4-methyl-1-(5-nitro-thiazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine; Ethyl ester [2-({4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-amino)-thiazole-4 -yl]-acetic acid; 4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-methanesulfonyl-phenyl)-amide; 4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid thiazol-2-ylamide; 4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (4-cyano-phenyl)-amide; {4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-pyrrolidin-1-yl-methanone; (2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-sulfonyl}-ethyl)-amide furan-2-carboxylic acids; {4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl} (tetrahydro-furan-3-yl)-methanone; 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid isoxazol-3-ylamide; 4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (6-cyano-pyridin-3-yl)amide; 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl- 5'-carbonitrile; (4-methyl-thiazol-2-yl)-amide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic group; 2-cyclopropyl-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone; Cyclopentyl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone; 4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (3-methyl-isoxazol-4-yl)-amide; [4-({4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-amino)-phenyl]-acetic acid ; [1-(5-amino-thiazol-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine; 4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid (3-methyl-isothiazol-5-yl)-amide; 3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-cyclopentanone; 4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid benzyl-methyl-amide; and 4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid dimethylamide; 22. Pharmaceutical preparation for (a) treatment or prevention of disorders or conditions selected from organ transplant rejection, xenogeneic transplant, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications resulting from diabetes, cancer, asthma, atopic dermatitis, autoimmune disorders of the thyroid, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune disorders, or (b) inhibition of protein kinases or Janus kinase 3 (JAK3), in mammals, including humans, indicated by containing the amount of the compound according to the patent of claim 1 or a pharmaceutically acceptable salt thereof, which is effective in such disorders or conditions, and a pharmaceutically acceptable carrier. 23. Pharmaceutical preparation for (a) treatment or prevention of disorders or conditions selected from organ transplant rejection, xenogeneic transplant, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications resulting from diabetes, cancer, asthma, atopic dermatitis, autoimmune disorders of the thyroid, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune disorders, or (b) inhibition of protein kinases or Janus kinase 3 (JAK3), in mammals, including humans, indicated by containing the amount of the compound according to the patent claim 1 or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional agents that modulate the mammalian immune system or with anti-inflammatory agents, which is effective in such disorders or conditions, and a pharmaceutically acceptable carrier. 24. Method of inhibiting protein kinases or Janus kinase 3 (JAK3) in mammals, including humans, characterized in that it consists in applying to said mammal an effective amount of the compound according to patent claim 1 or its pharmaceutically acceptable salt. 25. Procedure for treating or preventing disorders or conditions selected from rejection of an organ transplant, xenogeneic transplant, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications resulting from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune disorders, in mammals, including humans, characterized by the fact that it consists in applying to said mammal an amount of the compound according to patent claim 1 or its pharmaceutically acceptable salt, which is effective in the treatment of such conditions . 26. A method of inhibiting protein kinases or Janus kinase 3 (JAK3) in a mammal, including a human, indicated by the fact that it consists in applying to said mammal an effective amount of the compound according to patent claim 1 or its pharmaceutically acceptable salt, alone or in combination with with one or more additional agents that modulate the mammalian immune system or with anti-inflammatory agents. 27. Procedure for treating or preventing disorders or conditions selected from rejection of an organ transplant, xenogeneic transplant, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications resulting from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune disorders, in mammals, including humans, characterized in that it consists in applying to said mammal an effective amount of the compound according to patent claim 1 or its pharmaceutically acceptable salt, alone or in combination with one or more additional agents that modulate the mammalian immune system or with anti-inflammatory agents.